BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer

Autor: Miguel Angel Molina-Vila, Emilio Bria, Daniela Morales-Espinosa, Elisabetta Crisetti, Carles Codony-Servat, Guillermo Lopez-Vivanco, Enriqueta Felip, Jordi Codony-Servat, Jose Luis Ramirez, Margarita Majem, Joaquim Bosch-Barrera, Andrés F. Cardona, Ana Giménez-Capitán, Rafael Rosell, Alain Vergnenegre, Niki Karachaliou, Mariacarmela Santarpia, José Javier Sánchez Hernández, Rosario García-Campelo, Isabella Sperduti, Enric Carcereny, Teresa Moran, Jordi Bertran-Alamillo, Sara Pilotto, Jose Miguel Sanchez, Santiago Viteri, Ana Drozdowskyj, Cristina Teixidó, Alberto Verlicchi, Filippo de Marinis, Bartomeu Massuti, Maria Gonzalez-Cao, Radj Gervais, Imane Chaib
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Male
Aged
Apoptosis
Apoptosis Regulatory Proteins
Carcinoma
Non-Small-Cell Lung
Cohort Studies
Disease-Free Survival
Erlotinib Hydrochloride
Female
Gene Expression Regulation
Neoplastic
Humans
Inhibitory Concentration 50
Lung Neoplasms
Membrane Proteins
Middle Aged
Mutation
Proto-Oncogene Proteins
Quinazolines
RNA
Messenger
Receptor
Epidermal Growth Factor
Signal Transduction
TOR Serine-Threonine Kinases
Treatment Outcome
Messenger
Tumour biomarkers
Non-Small-Cell Lung
Multidisciplinary
Bcl-2-Like Protein 11
Gefitinib
ErbB Receptors
Messenger-RNA-expression
mutations
chemotherapy
BRCA1
apoptosis
therapy
kinase
eurtac
Erlotinib
Signal transduction
medicine.drug
Receptor
medicine.medical_specialty
Biology
Article
Internal medicine
medicine
Lung cancer
neoplasms
PI3K/AKT/mTOR pathway
Neoplastic
Epidermal Growth Factor
Cell growth
Carcinoma
medicine.disease
respiratory tract diseases
Endocrinology
Gene Expression Regulation
Cancer research
RNA
Non-small-cell lung cancer
Zdroj: Scientific Reports
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
Instituto de Salud Carlos III (ISCIII)
SCIENTIFIC REPORTS
r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante
instname
Dipòsit Digital de Documents de la UAB
Universitat Autònoma de Barcelona
Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid
Consejería de Sanidad de la Comunidad de Madrid
ISSN: 2045-2322
Popis: BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR.
Databáze: OpenAIRE
Externí odkaz: